The long term objective of this project is to determine those factors in the maternal and fetal compartments responsible for maintaining and regulating uteroplacental (UtBF) and umbilicoplacental blood flow, and how they relate to general cardiovascular adaptation during pregnancy. In the proposed funding period, efforts will be focused on 3 main areas: the vascular effects of estrogen, angiotensin II (ANG II) receptor (ATR) expression and function, and smooth muscle protein expression and function. To do this 5 Specific Aims will be addressed: 1)to determine the role of nitric oxide, cGMP and K+ channels in mediating estrogen- induced vasodilation and modulation of UtBF in pregnancy; 2) to clarify what peripherally released vasoconstrictor(s) mediates ANG II induced uterine vasoconstriction; 3) to determine how vascular smooth muscle ATR expression is regulated in pregnancy; 4) to investigate the hormonal and/or growth factors and inhibitors of cell division that account for uterine vascular growth and hypertrophy in pregnancy; and 5) to examine the role and mechanism whereby estrogen may modulate uteroplacental and umbilicoplacental blood flows prior to and during parturition. To achieve these aims we will study chronically instrumented nonpregnant ewes and pregnant ewes with their fetus. In vivo studies are designed to answer specific questions about physiologic responses to and mechanisms of action by estrogen, ANG II or alpha-agonists in maternal uterine circulation, and the effects of parturition on both maternal and fetal placental vasculature. In vitro studies using tissues from these animals with patch-clamp techniques, contractile protein measurements, western or northern analysis, cell cultures, and measurement of vascular stresses will permit us to more accurately determine the cellular and molecular mechanisms responsible for adaptive changes to pregnancy. The results of the proposed studies will provide important insights into biochemical cellular and physiologic adaptive mechanisms that are necessary for the successful outcome of pregnancy and the maintenance of fetal well-being, which in turn will improve our understanding of problems associated with abnormal pregnancy and development, thereby permitting us to address them in a more meaningful way.